Nancy Walsh

BOSTON — The diagnosis of syphilis is often delayed in HIV-positive patients, as it is characterized by a wide range of symptoms that may not be recognized as infection with Treponema pallidum, according to Dr. Lawrence A. Siegel of the division of international medicine and infectious diseases, Cornell University, New York.

After declining to an all-time low in 2000, the rate of syphilis in the United States rose from 3 per 100,000 population in 2001 to 5.7 per 100,000 in 2006. Syphilis has increased particularly dramatically in men who have sex with men (MSM), who made up 4% of cases in 2000 but who represented 64% of cases in 2006, Dr. Siegel reported in a poster session at the 15th Conference on Retroviruses and Opportunistic Infections.

Nationwide, approximately 60% of cases of syphilis now are seen in HIV-positive, urban MSM, but in New York City, 97% of syphilis cases are in MSM.

To more fully characterize this coinfected population in New York City, Dr. Siegel and his colleagues undertook a retrospective chart review of all HIV-positive MSM diagnosed with incident syphilis at the Cornell HIV clinic between January 2001 and December 2007.

A total of 118 cases of syphilis were identified. Stage at diagnosis was primary in 8 patients, secondary in 80, early latent in 17, and late latent in 13, Dr. Siegel reported. Three patients had neurosyphilis.

Median age of the patients was 38 years. A total of 33% were white, 30% were black, 34% were Hispanic, and the rest were classified as “other.” The HIV RNA level was less than 400 copies/mL in 56%, and median CD4 count was 399 cells/mm

Clinical presentations were varied, and the diagnosis was delayed in nearly half of the patients overall. (See box.)

A total of 96% of patients had a fourfold decrease in RPR titer at 1 year, but reinfections were common, at a rate of 10% a year.

A multivariate analysis found that higher baseline RPR titer and diagnosis of latent syphilis were associated with a longer time until the RPR titer became negative, Dr. Siegel reported at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Different treatment regimens (one or three doses of 2.4 million U benzathine penicillin, or doxycycline 100 mg twice daily for 30 days) weren't tied to a longer time until RPR negativity, the researchers said. Cases of early syphilis in this population are often not identified, so a higher index of suspicion is needed. More frequent serologic testing also is warranted.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The diagnosis of syphilis is often delayed in HIV-positive patients, as it is characterized by a wide range of symptoms that may not be recognized as infection with Treponema pallidum, according to Dr. Lawrence A. Siegel of the division of international medicine and infectious diseases, Cornell University, New York.

After declining to an all-time low in 2000, the rate of syphilis in the United States rose from 3 per 100,000 population in 2001 to 5.7 per 100,000 in 2006. Syphilis has increased particularly dramatically in men who have sex with men (MSM), who made up 4% of cases in 2000 but who represented 64% of cases in 2006, Dr. Siegel reported in a poster session at the 15th Conference on Retroviruses and Opportunistic Infections.

Nationwide, approximately 60% of cases of syphilis now are seen in HIV-positive, urban MSM, but in New York City, 97% of syphilis cases are in MSM.

To more fully characterize this coinfected population in New York City, Dr. Siegel and his colleagues undertook a retrospective chart review of all HIV-positive MSM diagnosed with incident syphilis at the Cornell HIV clinic between January 2001 and December 2007.

A total of 118 cases of syphilis were identified. Stage at diagnosis was primary in 8 patients, secondary in 80, early latent in 17, and late latent in 13, Dr. Siegel reported. Three patients had neurosyphilis.

Median age of the patients was 38 years. A total of 33% were white, 30% were black, 34% were Hispanic, and the rest were classified as “other.” The HIV RNA level was less than 400 copies/mL in 56%, and median CD4 count was 399 cells/mm

Clinical presentations were varied, and the diagnosis was delayed in nearly half of the patients overall. (See box.)

A total of 96% of patients had a fourfold decrease in RPR titer at 1 year, but reinfections were common, at a rate of 10% a year.

A multivariate analysis found that higher baseline RPR titer and diagnosis of latent syphilis were associated with a longer time until the RPR titer became negative, Dr. Siegel reported at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Different treatment regimens (one or three doses of 2.4 million U benzathine penicillin, or doxycycline 100 mg twice daily for 30 days) weren't tied to a longer time until RPR negativity, the researchers said. Cases of early syphilis in this population are often not identified, so a higher index of suspicion is needed. More frequent serologic testing also is warranted.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The diagnosis of syphilis is often delayed in HIV-positive patients, as it is characterized by a wide range of symptoms that may not be recognized as infection with Treponema pallidum, according to Dr. Lawrence A. Siegel of the division of international medicine and infectious diseases, Cornell University, New York.

After declining to an all-time low in 2000, the rate of syphilis in the United States rose from 3 per 100,000 population in 2001 to 5.7 per 100,000 in 2006. Syphilis has increased particularly dramatically in men who have sex with men (MSM), who made up 4% of cases in 2000 but who represented 64% of cases in 2006, Dr. Siegel reported in a poster session at the 15th Conference on Retroviruses and Opportunistic Infections.

Nationwide, approximately 60% of cases of syphilis now are seen in HIV-positive, urban MSM, but in New York City, 97% of syphilis cases are in MSM.

To more fully characterize this coinfected population in New York City, Dr. Siegel and his colleagues undertook a retrospective chart review of all HIV-positive MSM diagnosed with incident syphilis at the Cornell HIV clinic between January 2001 and December 2007.

A total of 118 cases of syphilis were identified. Stage at diagnosis was primary in 8 patients, secondary in 80, early latent in 17, and late latent in 13, Dr. Siegel reported. Three patients had neurosyphilis.

Median age of the patients was 38 years. A total of 33% were white, 30% were black, 34% were Hispanic, and the rest were classified as “other.” The HIV RNA level was less than 400 copies/mL in 56%, and median CD4 count was 399 cells/mm

Clinical presentations were varied, and the diagnosis was delayed in nearly half of the patients overall. (See box.)

A total of 96% of patients had a fourfold decrease in RPR titer at 1 year, but reinfections were common, at a rate of 10% a year.

A multivariate analysis found that higher baseline RPR titer and diagnosis of latent syphilis were associated with a longer time until the RPR titer became negative, Dr. Siegel reported at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Different treatment regimens (one or three doses of 2.4 million U benzathine penicillin, or doxycycline 100 mg twice daily for 30 days) weren't tied to a longer time until RPR negativity, the researchers said. Cases of early syphilis in this population are often not identified, so a higher index of suspicion is needed. More frequent serologic testing also is warranted.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — An increased risk for osteoporosis or osteopenia is among the age-related complications faced by patients surviving long term with HIV disease.

Cross-sectional studies have shown that patients with HIV have a greater prevalence of reduced bone mineral density, compared with healthy controls, but longitudinal data that would demonstrate the significance of this increased risk are lacking, said Dr. William G. Powderly of University College Dublin.

To meet this need for data, the Centers for Disease Control and Prevention is prospectively following a cohort of more than 500 HIV-infected patients in the Study to Understand the Natural History of HIV and AIDS (SUN), Dr. Powderly said at the 15th Conference on Retroviruses and Opportunistic Infections.

On enrollment in SUN, patients had baseline bone densitometry and body composition measurements, clinical data, and fasting laboratory data collected, and were matched for age, race, sex, and body mass index with controls from the National Health and Nutrition Examination Study III.

Among the SUN patients (mean age 41 years), 52% had osteopenia and 10% had frank osteoporosis, Dr. Powderly said. A total of 78% were men, 25% were black, and almost 80% were receiving antiretroviral therapy.

Analysis revealed that factors associated with an increased risk of low bone mineral density included age over 45 years (odds ratio 2.35) and CD4 count below 300 cells/mm

Duration of HIV infection longer than 98 months also was associated with an increased risk (OR 1.56).

Determining whether bone mineral loss will continue over time and translate into increased risk for fractures is a “critically important” area of HIV research, Dr. Powderly said at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the CDC.

Aside from risk factors also present in the general population such as smoking, alcohol use, low body mass index, and lack of physical activity, the aging HIV patient also might have renal dysfunction and inadequate nutrition, which can further contribute to bone loss.

HIV disease itself might alter the processes involved in bone mineralization and turnover, according to Dr. Powderly. In a study he and his colleagues performed, human osteoblast and mesenchymal stem cell lines were treated in vitro with several HIV proteins. Exposure to these proteins reduced calcium deposition, alkaline phosphatase activity, and mRNA levels of osteogenic transcription factors in osteoblasts, and the ability of stem cells to develop into osteoblasts was modulated (AIDS Res. Hum. Retroviruses 2007;23:1521–30).

There is also some evidence implicating potent antiretroviral medications in bone loss. In a meta-analysis of 20 studies that included 884 patients, 67% had reduced bone mineral density and 15% had osteoporosis. Those receiving antiretroviral therapy had a 2.5-fold increased risk of having reduced bone mineral density, compared with those who were treatment naive (AIDS 2006;20:2165–74).

The dynamic process of bone mineralization is another factor. “We reach the peak of bone mineralization at around 30 years, and then both men and women lose bone at a rate of approximately 0.5%–1% per year,” he said. “But we have no data on peak bone mineralization in HIV patients. It's quite possible that the high rates of osteoporosis and osteopenia we are seeing in these patients is not a result of accelerated bone mineral loss but because for some reason they never reached the same peak mineralization as healthy individuals,” Dr. Powderly said.

“Sorting out risk factors, the HIV effects, and the treatment effects in such a multifactorial situation is not going to be easy,” he noted.

Until the relative contributions to bone loss of the various factors can be clarified, the routine care of older patients with HIV should include monitoring of markers of bone turnover, he said.

BOSTON — An increased risk for osteoporosis or osteopenia is among the age-related complications faced by patients surviving long term with HIV disease.

Cross-sectional studies have shown that patients with HIV have a greater prevalence of reduced bone mineral density, compared with healthy controls, but longitudinal data that would demonstrate the significance of this increased risk are lacking, said Dr. William G. Powderly of University College Dublin.

To meet this need for data, the Centers for Disease Control and Prevention is prospectively following a cohort of more than 500 HIV-infected patients in the Study to Understand the Natural History of HIV and AIDS (SUN), Dr. Powderly said at the 15th Conference on Retroviruses and Opportunistic Infections.

On enrollment in SUN, patients had baseline bone densitometry and body composition measurements, clinical data, and fasting laboratory data collected, and were matched for age, race, sex, and body mass index with controls from the National Health and Nutrition Examination Study III.

Among the SUN patients (mean age 41 years), 52% had osteopenia and 10% had frank osteoporosis, Dr. Powderly said. A total of 78% were men, 25% were black, and almost 80% were receiving antiretroviral therapy.

Analysis revealed that factors associated with an increased risk of low bone mineral density included age over 45 years (odds ratio 2.35) and CD4 count below 300 cells/mm

Duration of HIV infection longer than 98 months also was associated with an increased risk (OR 1.56).

Determining whether bone mineral loss will continue over time and translate into increased risk for fractures is a “critically important” area of HIV research, Dr. Powderly said at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the CDC.

Aside from risk factors also present in the general population such as smoking, alcohol use, low body mass index, and lack of physical activity, the aging HIV patient also might have renal dysfunction and inadequate nutrition, which can further contribute to bone loss.

HIV disease itself might alter the processes involved in bone mineralization and turnover, according to Dr. Powderly. In a study he and his colleagues performed, human osteoblast and mesenchymal stem cell lines were treated in vitro with several HIV proteins. Exposure to these proteins reduced calcium deposition, alkaline phosphatase activity, and mRNA levels of osteogenic transcription factors in osteoblasts, and the ability of stem cells to develop into osteoblasts was modulated (AIDS Res. Hum. Retroviruses 2007;23:1521–30).

There is also some evidence implicating potent antiretroviral medications in bone loss. In a meta-analysis of 20 studies that included 884 patients, 67% had reduced bone mineral density and 15% had osteoporosis. Those receiving antiretroviral therapy had a 2.5-fold increased risk of having reduced bone mineral density, compared with those who were treatment naive (AIDS 2006;20:2165–74).

The dynamic process of bone mineralization is another factor. “We reach the peak of bone mineralization at around 30 years, and then both men and women lose bone at a rate of approximately 0.5%–1% per year,” he said. “But we have no data on peak bone mineralization in HIV patients. It's quite possible that the high rates of osteoporosis and osteopenia we are seeing in these patients is not a result of accelerated bone mineral loss but because for some reason they never reached the same peak mineralization as healthy individuals,” Dr. Powderly said.

“Sorting out risk factors, the HIV effects, and the treatment effects in such a multifactorial situation is not going to be easy,” he noted.

Until the relative contributions to bone loss of the various factors can be clarified, the routine care of older patients with HIV should include monitoring of markers of bone turnover, he said.

BOSTON — An increased risk for osteoporosis or osteopenia is among the age-related complications faced by patients surviving long term with HIV disease.

Cross-sectional studies have shown that patients with HIV have a greater prevalence of reduced bone mineral density, compared with healthy controls, but longitudinal data that would demonstrate the significance of this increased risk are lacking, said Dr. William G. Powderly of University College Dublin.

To meet this need for data, the Centers for Disease Control and Prevention is prospectively following a cohort of more than 500 HIV-infected patients in the Study to Understand the Natural History of HIV and AIDS (SUN), Dr. Powderly said at the 15th Conference on Retroviruses and Opportunistic Infections.

On enrollment in SUN, patients had baseline bone densitometry and body composition measurements, clinical data, and fasting laboratory data collected, and were matched for age, race, sex, and body mass index with controls from the National Health and Nutrition Examination Study III.

Among the SUN patients (mean age 41 years), 52% had osteopenia and 10% had frank osteoporosis, Dr. Powderly said. A total of 78% were men, 25% were black, and almost 80% were receiving antiretroviral therapy.

Analysis revealed that factors associated with an increased risk of low bone mineral density included age over 45 years (odds ratio 2.35) and CD4 count below 300 cells/mm

Duration of HIV infection longer than 98 months also was associated with an increased risk (OR 1.56).

Determining whether bone mineral loss will continue over time and translate into increased risk for fractures is a “critically important” area of HIV research, Dr. Powderly said at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the CDC.

Aside from risk factors also present in the general population such as smoking, alcohol use, low body mass index, and lack of physical activity, the aging HIV patient also might have renal dysfunction and inadequate nutrition, which can further contribute to bone loss.

HIV disease itself might alter the processes involved in bone mineralization and turnover, according to Dr. Powderly. In a study he and his colleagues performed, human osteoblast and mesenchymal stem cell lines were treated in vitro with several HIV proteins. Exposure to these proteins reduced calcium deposition, alkaline phosphatase activity, and mRNA levels of osteogenic transcription factors in osteoblasts, and the ability of stem cells to develop into osteoblasts was modulated (AIDS Res. Hum. Retroviruses 2007;23:1521–30).

There is also some evidence implicating potent antiretroviral medications in bone loss. In a meta-analysis of 20 studies that included 884 patients, 67% had reduced bone mineral density and 15% had osteoporosis. Those receiving antiretroviral therapy had a 2.5-fold increased risk of having reduced bone mineral density, compared with those who were treatment naive (AIDS 2006;20:2165–74).

The dynamic process of bone mineralization is another factor. “We reach the peak of bone mineralization at around 30 years, and then both men and women lose bone at a rate of approximately 0.5%–1% per year,” he said. “But we have no data on peak bone mineralization in HIV patients. It's quite possible that the high rates of osteoporosis and osteopenia we are seeing in these patients is not a result of accelerated bone mineral loss but because for some reason they never reached the same peak mineralization as healthy individuals,” Dr. Powderly said.

“Sorting out risk factors, the HIV effects, and the treatment effects in such a multifactorial situation is not going to be easy,” he noted.

Until the relative contributions to bone loss of the various factors can be clarified, the routine care of older patients with HIV should include monitoring of markers of bone turnover, he said.

BOSTON — The adolescent HIV-1 epidemic as reflected in a multisite cohort of U.S. youth is changing from one of vertically transmitted infection to one of infection acquired via risk behaviors, posing new challenges for providers and the health care system, Dr. Allison L. Agwu reported in a poster session at the 15th Conference on Retroviruses and Opportunistic Infections.

The HIV Research Network, a consortium of 21 clinical sites that provide primary HIV care, includes 684 patients aged 12–24 years. Vertical transmission was the source of infection in 227 patients, while risk behaviors account for 457 cases, according to Dr. Agwu of Johns Hopkins University, Baltimore.

Analysis of data from this cohort showed that patients infected through risk behaviors are older, with a median age of 22 years, compared with a median age of 15 years among vertical-transmission patients. They also are more likely to be male. A total of 292 (64%) of the risk-behavior patients are male, as are 108 (48%) of the vertical-transmission patients.

Risk behaviors comprised men having sex with men (51%), unprotected heterosexual activity (45%), and intravenous drug use (4%). The median CD4 count in the risk-behavior group was 492 cells/mm

Despite this worse immune suppression and higher levels of viremia among the risk-behavior patients, they were less likely to be on highly active antiretroviral therapy (HAART) (43% versus 88%), Dr. Agwu found. Those infected through risk behaviors also had significantly fewer outpatient visits, averaging five visits per year, while vertical-transmission patients averaged seven visits.

Rates of hospitalization did not differ, at 19/100 patient-years in the risk-behavior group and 17/100 patient-years in the vertical-transmission group, Dr. Agwu reported at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Other aspects of treatment also did not differ significantly between the two groups. For example, 89% of patients meeting the criteria for prophylaxis against Pneumocystis carinii pneumonia in the risk-behavior group received prophylaxis, as did 80% of vertical-transmission patients. Prophylaxis against Mycobacterium avium complex recommendations were followed by 83% and 75% of those in the risk-behavior and vertical-transmission groups, respectively.

“We suspect that there may be differences in psychosocial risk factors between the two groups that may account for the varying rates of HAART utilization,” Dr. Agwu said in an interview. “Our future questions will focus on deciphering both patient and provider barriers to HAART initiation in the risk behavior group in order to institute appropriate interventions,” she said.

She added that this group of patients in need of treatment is likely to grow in number as the CDC's recommendation of universal opt-out testing is implemented.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The adolescent HIV-1 epidemic as reflected in a multisite cohort of U.S. youth is changing from one of vertically transmitted infection to one of infection acquired via risk behaviors, posing new challenges for providers and the health care system, Dr. Allison L. Agwu reported in a poster session at the 15th Conference on Retroviruses and Opportunistic Infections.

The HIV Research Network, a consortium of 21 clinical sites that provide primary HIV care, includes 684 patients aged 12–24 years. Vertical transmission was the source of infection in 227 patients, while risk behaviors account for 457 cases, according to Dr. Agwu of Johns Hopkins University, Baltimore.

Analysis of data from this cohort showed that patients infected through risk behaviors are older, with a median age of 22 years, compared with a median age of 15 years among vertical-transmission patients. They also are more likely to be male. A total of 292 (64%) of the risk-behavior patients are male, as are 108 (48%) of the vertical-transmission patients.

Risk behaviors comprised men having sex with men (51%), unprotected heterosexual activity (45%), and intravenous drug use (4%). The median CD4 count in the risk-behavior group was 492 cells/mm

Despite this worse immune suppression and higher levels of viremia among the risk-behavior patients, they were less likely to be on highly active antiretroviral therapy (HAART) (43% versus 88%), Dr. Agwu found. Those infected through risk behaviors also had significantly fewer outpatient visits, averaging five visits per year, while vertical-transmission patients averaged seven visits.

Rates of hospitalization did not differ, at 19/100 patient-years in the risk-behavior group and 17/100 patient-years in the vertical-transmission group, Dr. Agwu reported at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Other aspects of treatment also did not differ significantly between the two groups. For example, 89% of patients meeting the criteria for prophylaxis against Pneumocystis carinii pneumonia in the risk-behavior group received prophylaxis, as did 80% of vertical-transmission patients. Prophylaxis against Mycobacterium avium complex recommendations were followed by 83% and 75% of those in the risk-behavior and vertical-transmission groups, respectively.

“We suspect that there may be differences in psychosocial risk factors between the two groups that may account for the varying rates of HAART utilization,” Dr. Agwu said in an interview. “Our future questions will focus on deciphering both patient and provider barriers to HAART initiation in the risk behavior group in order to institute appropriate interventions,” she said.

She added that this group of patients in need of treatment is likely to grow in number as the CDC's recommendation of universal opt-out testing is implemented.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The adolescent HIV-1 epidemic as reflected in a multisite cohort of U.S. youth is changing from one of vertically transmitted infection to one of infection acquired via risk behaviors, posing new challenges for providers and the health care system, Dr. Allison L. Agwu reported in a poster session at the 15th Conference on Retroviruses and Opportunistic Infections.

The HIV Research Network, a consortium of 21 clinical sites that provide primary HIV care, includes 684 patients aged 12–24 years. Vertical transmission was the source of infection in 227 patients, while risk behaviors account for 457 cases, according to Dr. Agwu of Johns Hopkins University, Baltimore.

Analysis of data from this cohort showed that patients infected through risk behaviors are older, with a median age of 22 years, compared with a median age of 15 years among vertical-transmission patients. They also are more likely to be male. A total of 292 (64%) of the risk-behavior patients are male, as are 108 (48%) of the vertical-transmission patients.

Risk behaviors comprised men having sex with men (51%), unprotected heterosexual activity (45%), and intravenous drug use (4%). The median CD4 count in the risk-behavior group was 492 cells/mm

Despite this worse immune suppression and higher levels of viremia among the risk-behavior patients, they were less likely to be on highly active antiretroviral therapy (HAART) (43% versus 88%), Dr. Agwu found. Those infected through risk behaviors also had significantly fewer outpatient visits, averaging five visits per year, while vertical-transmission patients averaged seven visits.

Rates of hospitalization did not differ, at 19/100 patient-years in the risk-behavior group and 17/100 patient-years in the vertical-transmission group, Dr. Agwu reported at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Other aspects of treatment also did not differ significantly between the two groups. For example, 89% of patients meeting the criteria for prophylaxis against Pneumocystis carinii pneumonia in the risk-behavior group received prophylaxis, as did 80% of vertical-transmission patients. Prophylaxis against Mycobacterium avium complex recommendations were followed by 83% and 75% of those in the risk-behavior and vertical-transmission groups, respectively.

“We suspect that there may be differences in psychosocial risk factors between the two groups that may account for the varying rates of HAART utilization,” Dr. Agwu said in an interview. “Our future questions will focus on deciphering both patient and provider barriers to HAART initiation in the risk behavior group in order to institute appropriate interventions,” she said.

She added that this group of patients in need of treatment is likely to grow in number as the CDC's recommendation of universal opt-out testing is implemented.

ELSEVIER GLOBAL MEDICAL NEWS

NEW YORK — A new treatment paradigm for benign prostatic hyperplasia is on the horizon.

During the past 2 decades, there has been a shift in the management of benign prostatic hyperplasia (BPH) away from surgery and toward earlier medical intervention, but standard treatment with the α₁-adrenergic receptor antagonists and the 5α-reductase inhibitors leaves a significant cohort of nonresponders, Dr. Herbert Lepor said at a meeting on adult and pediatric urology sponsored by New York University.

Among the limitations for α-blockers are safety concerns in patients with low blood pressure and orthostatic hypotension. The α-reductase inhibitors also have a slow onset of action and undesirable side effects, including loss of libido and erectile dysfunction. Moreover, compliance with daily regimens has been low, Dr. Lepor said.

A new approach to the medical management of lower urinary tract symptoms (LUTS) secondary to BPH uses a gonado- tropin-releasing hormone (GnRH) antagonist such as cetrorelix. Unlike the GnRH agonists used for prostate cancer, GnRH antagonists lower serum testosterone only partially and in a dose-dependent manner.

The GnRH antagonist is used to reach a level of androgen suppression that will shrink the prostate and improve clinical symptoms without the side effects associated with complete testosterone suppression, said Dr. Lepor, professor and Martin Spatz chairman of the department of urology at the university.

In phase II studies evaluating various doses, regimens, and two different formulations of cetrorelix, statistically significant differences from baseline and compared with placebo were seen on the primary end point of International Prostate Symptom Score (IPSS) at week 12. In one of these trials, 140 patients were randomized to receive cetrorelix acetate in four doses of 5 mg or 10 mg at 7-day intervals, two doses of 10 mg at 14-day intervals, or placebo. Improvements on IPSS of three to four symptom units were already noted at week 4. Mean baseline flow rate was about 9 ng/mL and rose to about 13 ng/mL in those in the active treatment groups.

With regard to prostate size, the results were not significant, although there was a trend to decrease in prostate volume. Testosterone levels during the 4-week injection period showed decreases of about 25%, and returned to baseline after the last injection. There was no effect on erectile function.

A second phase II trial randomized 250 patients to placebo or cetrorelix pamoate in two doses of 30 mg, three doses of 30 mg, one of 60 mg followed by another of 30 mg, or 60 mg followed by 60 mg. Doses were given at 14-day intervals. The results echoed those in the previous trial, with statistically significant dose-related improvements reported on the IPSS and on urinary flow rates, and responses persisting out to 120 days. In none of the groups were castration-level testosterone suppression or associated adverse effects seen.

A phase III study randomizing patients with BPH and voiding symptoms to cetrorelix pamoate is underway. Dr. Lepor disclosed he is a consultant to Æterna Zentaris Inc., the study sponsor.

NEW YORK — A new treatment paradigm for benign prostatic hyperplasia is on the horizon.

During the past 2 decades, there has been a shift in the management of benign prostatic hyperplasia (BPH) away from surgery and toward earlier medical intervention, but standard treatment with the α₁-adrenergic receptor antagonists and the 5α-reductase inhibitors leaves a significant cohort of nonresponders, Dr. Herbert Lepor said at a meeting on adult and pediatric urology sponsored by New York University.

Among the limitations for α-blockers are safety concerns in patients with low blood pressure and orthostatic hypotension. The α-reductase inhibitors also have a slow onset of action and undesirable side effects, including loss of libido and erectile dysfunction. Moreover, compliance with daily regimens has been low, Dr. Lepor said.

A new approach to the medical management of lower urinary tract symptoms (LUTS) secondary to BPH uses a gonado- tropin-releasing hormone (GnRH) antagonist such as cetrorelix. Unlike the GnRH agonists used for prostate cancer, GnRH antagonists lower serum testosterone only partially and in a dose-dependent manner.

The GnRH antagonist is used to reach a level of androgen suppression that will shrink the prostate and improve clinical symptoms without the side effects associated with complete testosterone suppression, said Dr. Lepor, professor and Martin Spatz chairman of the department of urology at the university.

In phase II studies evaluating various doses, regimens, and two different formulations of cetrorelix, statistically significant differences from baseline and compared with placebo were seen on the primary end point of International Prostate Symptom Score (IPSS) at week 12. In one of these trials, 140 patients were randomized to receive cetrorelix acetate in four doses of 5 mg or 10 mg at 7-day intervals, two doses of 10 mg at 14-day intervals, or placebo. Improvements on IPSS of three to four symptom units were already noted at week 4. Mean baseline flow rate was about 9 ng/mL and rose to about 13 ng/mL in those in the active treatment groups.

With regard to prostate size, the results were not significant, although there was a trend to decrease in prostate volume. Testosterone levels during the 4-week injection period showed decreases of about 25%, and returned to baseline after the last injection. There was no effect on erectile function.

A second phase II trial randomized 250 patients to placebo or cetrorelix pamoate in two doses of 30 mg, three doses of 30 mg, one of 60 mg followed by another of 30 mg, or 60 mg followed by 60 mg. Doses were given at 14-day intervals. The results echoed those in the previous trial, with statistically significant dose-related improvements reported on the IPSS and on urinary flow rates, and responses persisting out to 120 days. In none of the groups were castration-level testosterone suppression or associated adverse effects seen.

A phase III study randomizing patients with BPH and voiding symptoms to cetrorelix pamoate is underway. Dr. Lepor disclosed he is a consultant to Æterna Zentaris Inc., the study sponsor.

NEW YORK — A new treatment paradigm for benign prostatic hyperplasia is on the horizon.

During the past 2 decades, there has been a shift in the management of benign prostatic hyperplasia (BPH) away from surgery and toward earlier medical intervention, but standard treatment with the α₁-adrenergic receptor antagonists and the 5α-reductase inhibitors leaves a significant cohort of nonresponders, Dr. Herbert Lepor said at a meeting on adult and pediatric urology sponsored by New York University.

Among the limitations for α-blockers are safety concerns in patients with low blood pressure and orthostatic hypotension. The α-reductase inhibitors also have a slow onset of action and undesirable side effects, including loss of libido and erectile dysfunction. Moreover, compliance with daily regimens has been low, Dr. Lepor said.

A new approach to the medical management of lower urinary tract symptoms (LUTS) secondary to BPH uses a gonado- tropin-releasing hormone (GnRH) antagonist such as cetrorelix. Unlike the GnRH agonists used for prostate cancer, GnRH antagonists lower serum testosterone only partially and in a dose-dependent manner.

The GnRH antagonist is used to reach a level of androgen suppression that will shrink the prostate and improve clinical symptoms without the side effects associated with complete testosterone suppression, said Dr. Lepor, professor and Martin Spatz chairman of the department of urology at the university.

In phase II studies evaluating various doses, regimens, and two different formulations of cetrorelix, statistically significant differences from baseline and compared with placebo were seen on the primary end point of International Prostate Symptom Score (IPSS) at week 12. In one of these trials, 140 patients were randomized to receive cetrorelix acetate in four doses of 5 mg or 10 mg at 7-day intervals, two doses of 10 mg at 14-day intervals, or placebo. Improvements on IPSS of three to four symptom units were already noted at week 4. Mean baseline flow rate was about 9 ng/mL and rose to about 13 ng/mL in those in the active treatment groups.

With regard to prostate size, the results were not significant, although there was a trend to decrease in prostate volume. Testosterone levels during the 4-week injection period showed decreases of about 25%, and returned to baseline after the last injection. There was no effect on erectile function.

A second phase II trial randomized 250 patients to placebo or cetrorelix pamoate in two doses of 30 mg, three doses of 30 mg, one of 60 mg followed by another of 30 mg, or 60 mg followed by 60 mg. Doses were given at 14-day intervals. The results echoed those in the previous trial, with statistically significant dose-related improvements reported on the IPSS and on urinary flow rates, and responses persisting out to 120 days. In none of the groups were castration-level testosterone suppression or associated adverse effects seen.

A phase III study randomizing patients with BPH and voiding symptoms to cetrorelix pamoate is underway. Dr. Lepor disclosed he is a consultant to Æterna Zentaris Inc., the study sponsor.

BOSTON – The safety and efficacy of abatacept were maintained throughout 5 years of treatment for patients with rheumatoid arthritis, with more than one-third of those who remained in the long-term extension phase of a multicenter trial achieving an ACR 70 response.

The initial double-blind trial enrolled 339 patients with rheumatoid arthritis (RA) who had had an inadequate response to methotrexate, randomizing them to receive 2 mg/kg abatacept, 10 mg/kg abatacept, or placebo for 1 year. They also received background methotrexate in doses of 10-30 mg/week, Dr. Rene R. Westhovens reported in a poster session at the annual meeting of the American College of Rheumatology.

Abatacept was given as a 30-minute infusion on days 1, 15, and 30, and every 30 days thereafter.

By week 52, 63% of patients receiving the higher dose of abatacept had achieved an ACR 20 response, compared with 36% of those receiving placebo. Moreover, 42% and 21% of those receiving 10 mg/kg of the active drug achieved ACR 50 and 70 responses, respectively, compared with 20% and 8% of those receiving placebo (Arthritis Rheum. 2005;52:2263-71).

Of the 235 patients who completed the double-blind phase of the trial, 219 entered the long-term open-label phase, during which all participants received the 10-mg/kg dose of abatacept plus methotrexate. Among these 219 patients, 84, 68, and 67 were from the original 10-mg/kg, 2-mg/kg, and placebo groups, respectively. Their mean age was 56 years, 74% were female, and their mean disease duration was 10 years. At 5 years, 130 (59%) remained on the drug, reported Dr. Westhovens of University Hospital Gasthuisberg Leuven (Belgium).

The improvements in ACR 20, ACR 50, and ACR 70 responses seen in the 10-mg/kg group in the blinded phase of the trial were maintained at year 5, with response rates of 83%, 65%, and 40%.

During the blinded phase, 55% of patients in the 10-mg/kg group had clinically meaningful improvements in physical function, defined as an increase of 0.3 units or more on the modified Health Assessment Questionnaire Disability Index. This was maintained by 53% at year 5.

The types and incidence of serious adverse events were similar in the double-blind and 5-year cumulative study periods, according to Dr. Westhovens. There were 20 serious adverse events per 100 patient-years reported among patients receiving the active treatment during the double-blind phase of the trial, and 19 serious adverse events per 100 patient-years during the open-label phase.

With almost 60% of patients still participating in the study at 5 years, responses remain durable, demonstrating that “abatacept provides long-term clinical benefits to patients with active RA,” Dr. Westhovens wrote.

He disclosed that he received consulting fees from Bristol-Myers Squibb Co., the sponsor of the study.

BOSTON – The safety and efficacy of abatacept were maintained throughout 5 years of treatment for patients with rheumatoid arthritis, with more than one-third of those who remained in the long-term extension phase of a multicenter trial achieving an ACR 70 response.

The initial double-blind trial enrolled 339 patients with rheumatoid arthritis (RA) who had had an inadequate response to methotrexate, randomizing them to receive 2 mg/kg abatacept, 10 mg/kg abatacept, or placebo for 1 year. They also received background methotrexate in doses of 10-30 mg/week, Dr. Rene R. Westhovens reported in a poster session at the annual meeting of the American College of Rheumatology.

Abatacept was given as a 30-minute infusion on days 1, 15, and 30, and every 30 days thereafter.

By week 52, 63% of patients receiving the higher dose of abatacept had achieved an ACR 20 response, compared with 36% of those receiving placebo. Moreover, 42% and 21% of those receiving 10 mg/kg of the active drug achieved ACR 50 and 70 responses, respectively, compared with 20% and 8% of those receiving placebo (Arthritis Rheum. 2005;52:2263-71).

Of the 235 patients who completed the double-blind phase of the trial, 219 entered the long-term open-label phase, during which all participants received the 10-mg/kg dose of abatacept plus methotrexate. Among these 219 patients, 84, 68, and 67 were from the original 10-mg/kg, 2-mg/kg, and placebo groups, respectively. Their mean age was 56 years, 74% were female, and their mean disease duration was 10 years. At 5 years, 130 (59%) remained on the drug, reported Dr. Westhovens of University Hospital Gasthuisberg Leuven (Belgium).

The improvements in ACR 20, ACR 50, and ACR 70 responses seen in the 10-mg/kg group in the blinded phase of the trial were maintained at year 5, with response rates of 83%, 65%, and 40%.

During the blinded phase, 55% of patients in the 10-mg/kg group had clinically meaningful improvements in physical function, defined as an increase of 0.3 units or more on the modified Health Assessment Questionnaire Disability Index. This was maintained by 53% at year 5.

The types and incidence of serious adverse events were similar in the double-blind and 5-year cumulative study periods, according to Dr. Westhovens. There were 20 serious adverse events per 100 patient-years reported among patients receiving the active treatment during the double-blind phase of the trial, and 19 serious adverse events per 100 patient-years during the open-label phase.

With almost 60% of patients still participating in the study at 5 years, responses remain durable, demonstrating that “abatacept provides long-term clinical benefits to patients with active RA,” Dr. Westhovens wrote.

He disclosed that he received consulting fees from Bristol-Myers Squibb Co., the sponsor of the study.

BOSTON – The safety and efficacy of abatacept were maintained throughout 5 years of treatment for patients with rheumatoid arthritis, with more than one-third of those who remained in the long-term extension phase of a multicenter trial achieving an ACR 70 response.

The initial double-blind trial enrolled 339 patients with rheumatoid arthritis (RA) who had had an inadequate response to methotrexate, randomizing them to receive 2 mg/kg abatacept, 10 mg/kg abatacept, or placebo for 1 year. They also received background methotrexate in doses of 10-30 mg/week, Dr. Rene R. Westhovens reported in a poster session at the annual meeting of the American College of Rheumatology.

Abatacept was given as a 30-minute infusion on days 1, 15, and 30, and every 30 days thereafter.

By week 52, 63% of patients receiving the higher dose of abatacept had achieved an ACR 20 response, compared with 36% of those receiving placebo. Moreover, 42% and 21% of those receiving 10 mg/kg of the active drug achieved ACR 50 and 70 responses, respectively, compared with 20% and 8% of those receiving placebo (Arthritis Rheum. 2005;52:2263-71).

Of the 235 patients who completed the double-blind phase of the trial, 219 entered the long-term open-label phase, during which all participants received the 10-mg/kg dose of abatacept plus methotrexate. Among these 219 patients, 84, 68, and 67 were from the original 10-mg/kg, 2-mg/kg, and placebo groups, respectively. Their mean age was 56 years, 74% were female, and their mean disease duration was 10 years. At 5 years, 130 (59%) remained on the drug, reported Dr. Westhovens of University Hospital Gasthuisberg Leuven (Belgium).

The improvements in ACR 20, ACR 50, and ACR 70 responses seen in the 10-mg/kg group in the blinded phase of the trial were maintained at year 5, with response rates of 83%, 65%, and 40%.

During the blinded phase, 55% of patients in the 10-mg/kg group had clinically meaningful improvements in physical function, defined as an increase of 0.3 units or more on the modified Health Assessment Questionnaire Disability Index. This was maintained by 53% at year 5.

The types and incidence of serious adverse events were similar in the double-blind and 5-year cumulative study periods, according to Dr. Westhovens. There were 20 serious adverse events per 100 patient-years reported among patients receiving the active treatment during the double-blind phase of the trial, and 19 serious adverse events per 100 patient-years during the open-label phase.

With almost 60% of patients still participating in the study at 5 years, responses remain durable, demonstrating that “abatacept provides long-term clinical benefits to patients with active RA,” Dr. Westhovens wrote.

He disclosed that he received consulting fees from Bristol-Myers Squibb Co., the sponsor of the study.

NEW YORK — Intramyocardial delivery of bone marrow stem cells during coronary artery bypass grafting conferred additional benefits in ejection fraction and perfusion beyond that seen with the surgery alone in two small studies, Dr. Gustav Steinhoff reported at a conference on cell therapy and cardiovascular diseases.

The first was a phase I trial that included 15 patients with chronic ischemia resulting from previous myocardial infarction. Their mean age was 63 years, and all were male and had moderate to severe symptoms of coronary artery disease, including reduced exercise capacity and chest pain.

All patients first underwent bone marrow aspiration, and from the aspirate, CD133+ cells were isolated. CD133+ cells are a subset of CD34+ hematopoietic progenitor cells that have been found to improve myocardial function in animal models and to increase vascular differentiation, Dr. Steinhoff said.

The following day coronary artery bypass grafting (CABG) was done and the CD133+ cells were injected into an area of myocardial perfusion defect.

Among patients in this first trial, the average left ventricular ejection fraction (EF) evaluated echocardiographically increased significantly, from 39% to 50% at 6 months, and to 48% at 18 months. Left ventricular end systolic volume also decreased significantly, from 92 mL to 66 mL at 6 and 18 months, while end diastolic volume decreased from 144 mL to 121 mL at 6 months and to 127 mL at 18 months (J. Thorac. Cardiovasc. Surg. 2007;133:717–25).

All patients tolerated the procedure well, and there were no serious adverse events related to the treatment. One patient died of a stroke 9 months later.

The remaining 14 have survived for up to 5 years, for a total of 739 patient-years, said Dr. Steinhoff of the department of cardiac surgery, University of Rostock (Germany).

The promising results of the phase I study prompted Dr. Steinhoff and his colleagues to perform a phase II trial that included 55 patients who were randomized to stem cell therapy plus CABG or CABG alone. In this study, the mean age also was 63 years, and three-quarters of the patients were male. Disease severity was similar to that seen in the phase I trial.

Among patients who had the cell treatment, left ventricular EF increased from 37% to 47% at 6 months, while in the CABG-only patients it increased from 38% to 41% at 6 months. The difference between the groups was statistically significant, he said.

Moreover, gains in perfusion seen on single-photon emission CT scans were “long standing and impressive in many patients,” Dr. Steinhoff said. In one patient, perfusion had virtually normalized by 6 months, he noted.

Mean follow-up time now is 41 months in the cell therapy group and 39 months in the control CABG-only group. There have been two deaths in each group, for a mortality rate of 5.7% in the cell therapy group and 10% in the control group, Dr. Steinhoff said.

Additionally, two patients in the cell therapy group subsequently underwent percutaneous transluminal coronary angioplasty. Among the control patients, one has had a pulmonary embolism and another experienced cardiac decompensation.

“We concluded that safety and clinical feasibility was shown in the phase I trial, and that the phase II trial supported the safety and suggested clinical activity. We are now proceeding with a phase III trial scheduled to begin this year,” he said.

A total of 142 patients whose EF is 25%–30% will be enrolled, and the primary end point will be left ventricular EF at 6 months measured by cardiac magnetic resonance imaging.

But much remains to be done in the final development of this treatment, Dr. Steinhoff cautioned. Further efforts must include clarifying patient selection, assessing whether patients with worse preoperative left ventricular function derive more benefits, and confirming the long-term safety of the procedure.

ELSEVIER GLOBAL MEDICAL NEWS

NEW YORK — Intramyocardial delivery of bone marrow stem cells during coronary artery bypass grafting conferred additional benefits in ejection fraction and perfusion beyond that seen with the surgery alone in two small studies, Dr. Gustav Steinhoff reported at a conference on cell therapy and cardiovascular diseases.

The first was a phase I trial that included 15 patients with chronic ischemia resulting from previous myocardial infarction. Their mean age was 63 years, and all were male and had moderate to severe symptoms of coronary artery disease, including reduced exercise capacity and chest pain.

All patients first underwent bone marrow aspiration, and from the aspirate, CD133+ cells were isolated. CD133+ cells are a subset of CD34+ hematopoietic progenitor cells that have been found to improve myocardial function in animal models and to increase vascular differentiation, Dr. Steinhoff said.

The following day coronary artery bypass grafting (CABG) was done and the CD133+ cells were injected into an area of myocardial perfusion defect.

Among patients in this first trial, the average left ventricular ejection fraction (EF) evaluated echocardiographically increased significantly, from 39% to 50% at 6 months, and to 48% at 18 months. Left ventricular end systolic volume also decreased significantly, from 92 mL to 66 mL at 6 and 18 months, while end diastolic volume decreased from 144 mL to 121 mL at 6 months and to 127 mL at 18 months (J. Thorac. Cardiovasc. Surg. 2007;133:717–25).

All patients tolerated the procedure well, and there were no serious adverse events related to the treatment. One patient died of a stroke 9 months later.

The remaining 14 have survived for up to 5 years, for a total of 739 patient-years, said Dr. Steinhoff of the department of cardiac surgery, University of Rostock (Germany).

The promising results of the phase I study prompted Dr. Steinhoff and his colleagues to perform a phase II trial that included 55 patients who were randomized to stem cell therapy plus CABG or CABG alone. In this study, the mean age also was 63 years, and three-quarters of the patients were male. Disease severity was similar to that seen in the phase I trial.

Among patients who had the cell treatment, left ventricular EF increased from 37% to 47% at 6 months, while in the CABG-only patients it increased from 38% to 41% at 6 months. The difference between the groups was statistically significant, he said.

Moreover, gains in perfusion seen on single-photon emission CT scans were “long standing and impressive in many patients,” Dr. Steinhoff said. In one patient, perfusion had virtually normalized by 6 months, he noted.

Mean follow-up time now is 41 months in the cell therapy group and 39 months in the control CABG-only group. There have been two deaths in each group, for a mortality rate of 5.7% in the cell therapy group and 10% in the control group, Dr. Steinhoff said.

Additionally, two patients in the cell therapy group subsequently underwent percutaneous transluminal coronary angioplasty. Among the control patients, one has had a pulmonary embolism and another experienced cardiac decompensation.

“We concluded that safety and clinical feasibility was shown in the phase I trial, and that the phase II trial supported the safety and suggested clinical activity. We are now proceeding with a phase III trial scheduled to begin this year,” he said.

A total of 142 patients whose EF is 25%–30% will be enrolled, and the primary end point will be left ventricular EF at 6 months measured by cardiac magnetic resonance imaging.

But much remains to be done in the final development of this treatment, Dr. Steinhoff cautioned. Further efforts must include clarifying patient selection, assessing whether patients with worse preoperative left ventricular function derive more benefits, and confirming the long-term safety of the procedure.

ELSEVIER GLOBAL MEDICAL NEWS

NEW YORK — Intramyocardial delivery of bone marrow stem cells during coronary artery bypass grafting conferred additional benefits in ejection fraction and perfusion beyond that seen with the surgery alone in two small studies, Dr. Gustav Steinhoff reported at a conference on cell therapy and cardiovascular diseases.

The first was a phase I trial that included 15 patients with chronic ischemia resulting from previous myocardial infarction. Their mean age was 63 years, and all were male and had moderate to severe symptoms of coronary artery disease, including reduced exercise capacity and chest pain.

All patients first underwent bone marrow aspiration, and from the aspirate, CD133+ cells were isolated. CD133+ cells are a subset of CD34+ hematopoietic progenitor cells that have been found to improve myocardial function in animal models and to increase vascular differentiation, Dr. Steinhoff said.

The following day coronary artery bypass grafting (CABG) was done and the CD133+ cells were injected into an area of myocardial perfusion defect.

Among patients in this first trial, the average left ventricular ejection fraction (EF) evaluated echocardiographically increased significantly, from 39% to 50% at 6 months, and to 48% at 18 months. Left ventricular end systolic volume also decreased significantly, from 92 mL to 66 mL at 6 and 18 months, while end diastolic volume decreased from 144 mL to 121 mL at 6 months and to 127 mL at 18 months (J. Thorac. Cardiovasc. Surg. 2007;133:717–25).

All patients tolerated the procedure well, and there were no serious adverse events related to the treatment. One patient died of a stroke 9 months later.

The remaining 14 have survived for up to 5 years, for a total of 739 patient-years, said Dr. Steinhoff of the department of cardiac surgery, University of Rostock (Germany).

The promising results of the phase I study prompted Dr. Steinhoff and his colleagues to perform a phase II trial that included 55 patients who were randomized to stem cell therapy plus CABG or CABG alone. In this study, the mean age also was 63 years, and three-quarters of the patients were male. Disease severity was similar to that seen in the phase I trial.

Among patients who had the cell treatment, left ventricular EF increased from 37% to 47% at 6 months, while in the CABG-only patients it increased from 38% to 41% at 6 months. The difference between the groups was statistically significant, he said.

Moreover, gains in perfusion seen on single-photon emission CT scans were “long standing and impressive in many patients,” Dr. Steinhoff said. In one patient, perfusion had virtually normalized by 6 months, he noted.

Mean follow-up time now is 41 months in the cell therapy group and 39 months in the control CABG-only group. There have been two deaths in each group, for a mortality rate of 5.7% in the cell therapy group and 10% in the control group, Dr. Steinhoff said.

Additionally, two patients in the cell therapy group subsequently underwent percutaneous transluminal coronary angioplasty. Among the control patients, one has had a pulmonary embolism and another experienced cardiac decompensation.

“We concluded that safety and clinical feasibility was shown in the phase I trial, and that the phase II trial supported the safety and suggested clinical activity. We are now proceeding with a phase III trial scheduled to begin this year,” he said.

A total of 142 patients whose EF is 25%–30% will be enrolled, and the primary end point will be left ventricular EF at 6 months measured by cardiac magnetic resonance imaging.

But much remains to be done in the final development of this treatment, Dr. Steinhoff cautioned. Further efforts must include clarifying patient selection, assessing whether patients with worse preoperative left ventricular function derive more benefits, and confirming the long-term safety of the procedure.

ELSEVIER GLOBAL MEDICAL NEWS

NEW YORK — Therapeutic neovascularization through the intramyocardial administration of autologous CD34+ stem cells is a promising approach in patients with refractory ischemia, Dr. Timothy D. Henry said at a conference on cell therapy and cardiovascular diseases.

Many patients with severe coronary artery disease experience persistent, disabling angina despite the use of antianginal drugs and mechanical revascularization, and few good options exist for these patients at present, according to Dr. Henry, who is chief of research, Minneapolis Heart Research Foundation, Minneapolis.

Preclinical studies suggested that neovascularization is possible in chronic ischemia following the administration of autologous endothelial progenitor cells, and particularly when cells expressing the CD34+ marker were used. A pilot study has now provided evidence that such an approach is safe and may result in symptomatic improvements in angina symptoms, Dr. Henry said.

The double-blind, placebo-controlled study included 24 patients comprising 5 women and 19 men, whose mean age was 62 years. All had Canadian Cardiovascular Society (CCS) class III or IV angina, were not candidates for conventional revascularization, had failed on optimal medical therapy, and were on at least two antianginal medications.

Initially all patients underwent stem cell mobilization with the administration of granulocyte colony-stimulating factor for 5 days, at which time leukapheresis was performed and the CD34+ fraction of mononuclear cells were isolated.

They then underwent cardiac navigation using NOGA electromechanical mapping and intramyocardial injection of the CD34+ cells or placebo into the ischemic zone, and were followed for 12 months.

The treatment was well tolerated, with no serious adverse events being attributed to the cell therapy, Dr. Henry said. One patient in the placebo group developed ventricular tachycardia during the mapping procedure, but was cardioverted successfully.

At 3 months, the number of episodes of angina per week fell from 21 to 10 in the treated group, and rose from 21 to 27 in the placebo group. By 6 months, the number of episodes per week had fallen to 9 and 16 in the treated and placebo groups, respectively (Circulation 2007;115:3165–72).

By 6 months, 50% of patients in the treated group had experienced an improvement by at least two CCS classes, as had 33% of placebo patients.

Results on single-photon emission computed tomography (SPECT) were mixed, showing some improvement at 3 months but none at 6 months, Dr. Henry said. “One of the things holding us back in treating patients with chronic refractory ischemia is the lack of a gold standard to measure myocardial blood flow,” he said.

Moreover, improvements in exercise tolerance were modest at best, increasing 0.3 minutes and 0.5 minutes in the placebo and active treatment groups at 3 months, respectively.

Previous trials of various therapies for refractory angina also have failed to demonstrate improvements in exercise tolerance. For example, in an analysis of pooled data from the Angiogenic gene therapy (AGENT) 3 and 4 studies, which evaluated the intracoronary administration of Ad5FGF-4 in patients with chronic angina, there was no significant difference between the active treatment and placebo on the primary end point of change from baseline exercise time at 12 weeks. However, the incidence of angina and worsening angina was significantly less in patients receiving the gene therapy, at 18%, compared with those receiving placebo, at 25% (J. Am. Coll. Cardiol. 2007;50:1038–46).

“As far as placebo-controlled trials that show improvement in exercise time in patients with refractory angina, for angiogenesis there are none, for enhanced external counterpulsation there have been none, for percutaneous transmyocardial laser revascularization there have been none, and for novel drug therapy, there have been none,” Dr. Henry said. “If you ask the patients what the problem is, they say it's chest pain.”

Therefore, a larger randomized trial of CD34+ stem cells that has recently completed enrollment has, as its primary efficacy end point, frequency of angina episodes.

The study protocol calls for 150 patients aged 21–80 years who have CCS functional class III or IV refractory angina. Following the intramyocardial injection of autologous stem cells or placebo, patients will be followed up with MRI and SPECT at 6 and 12 months.

“It's important to remember that this is a very challenging patient population, where bypass didn't work, PCI didn't work, and medical therapy didn't work, and for whom we don't have great options now. Will CD34+ therapy be a better option? Certainly the phase I trial was suggestive, and we're excited about seeing the results of the phase II trial,” said Dr. Henry, who is a consultant to Baxter Healthcare, the study sponsor.

ELSEVIER GLOBAL MEDICAL NEWS

NEW YORK — Therapeutic neovascularization through the intramyocardial administration of autologous CD34+ stem cells is a promising approach in patients with refractory ischemia, Dr. Timothy D. Henry said at a conference on cell therapy and cardiovascular diseases.

Many patients with severe coronary artery disease experience persistent, disabling angina despite the use of antianginal drugs and mechanical revascularization, and few good options exist for these patients at present, according to Dr. Henry, who is chief of research, Minneapolis Heart Research Foundation, Minneapolis.

Preclinical studies suggested that neovascularization is possible in chronic ischemia following the administration of autologous endothelial progenitor cells, and particularly when cells expressing the CD34+ marker were used. A pilot study has now provided evidence that such an approach is safe and may result in symptomatic improvements in angina symptoms, Dr. Henry said.

The double-blind, placebo-controlled study included 24 patients comprising 5 women and 19 men, whose mean age was 62 years. All had Canadian Cardiovascular Society (CCS) class III or IV angina, were not candidates for conventional revascularization, had failed on optimal medical therapy, and were on at least two antianginal medications.

Initially all patients underwent stem cell mobilization with the administration of granulocyte colony-stimulating factor for 5 days, at which time leukapheresis was performed and the CD34+ fraction of mononuclear cells were isolated.

They then underwent cardiac navigation using NOGA electromechanical mapping and intramyocardial injection of the CD34+ cells or placebo into the ischemic zone, and were followed for 12 months.

The treatment was well tolerated, with no serious adverse events being attributed to the cell therapy, Dr. Henry said. One patient in the placebo group developed ventricular tachycardia during the mapping procedure, but was cardioverted successfully.

At 3 months, the number of episodes of angina per week fell from 21 to 10 in the treated group, and rose from 21 to 27 in the placebo group. By 6 months, the number of episodes per week had fallen to 9 and 16 in the treated and placebo groups, respectively (Circulation 2007;115:3165–72).

By 6 months, 50% of patients in the treated group had experienced an improvement by at least two CCS classes, as had 33% of placebo patients.

Results on single-photon emission computed tomography (SPECT) were mixed, showing some improvement at 3 months but none at 6 months, Dr. Henry said. “One of the things holding us back in treating patients with chronic refractory ischemia is the lack of a gold standard to measure myocardial blood flow,” he said.

Moreover, improvements in exercise tolerance were modest at best, increasing 0.3 minutes and 0.5 minutes in the placebo and active treatment groups at 3 months, respectively.

Previous trials of various therapies for refractory angina also have failed to demonstrate improvements in exercise tolerance. For example, in an analysis of pooled data from the Angiogenic gene therapy (AGENT) 3 and 4 studies, which evaluated the intracoronary administration of Ad5FGF-4 in patients with chronic angina, there was no significant difference between the active treatment and placebo on the primary end point of change from baseline exercise time at 12 weeks. However, the incidence of angina and worsening angina was significantly less in patients receiving the gene therapy, at 18%, compared with those receiving placebo, at 25% (J. Am. Coll. Cardiol. 2007;50:1038–46).

“As far as placebo-controlled trials that show improvement in exercise time in patients with refractory angina, for angiogenesis there are none, for enhanced external counterpulsation there have been none, for percutaneous transmyocardial laser revascularization there have been none, and for novel drug therapy, there have been none,” Dr. Henry said. “If you ask the patients what the problem is, they say it's chest pain.”

Therefore, a larger randomized trial of CD34+ stem cells that has recently completed enrollment has, as its primary efficacy end point, frequency of angina episodes.

The study protocol calls for 150 patients aged 21–80 years who have CCS functional class III or IV refractory angina. Following the intramyocardial injection of autologous stem cells or placebo, patients will be followed up with MRI and SPECT at 6 and 12 months.

“It's important to remember that this is a very challenging patient population, where bypass didn't work, PCI didn't work, and medical therapy didn't work, and for whom we don't have great options now. Will CD34+ therapy be a better option? Certainly the phase I trial was suggestive, and we're excited about seeing the results of the phase II trial,” said Dr. Henry, who is a consultant to Baxter Healthcare, the study sponsor.

ELSEVIER GLOBAL MEDICAL NEWS

NEW YORK — Therapeutic neovascularization through the intramyocardial administration of autologous CD34+ stem cells is a promising approach in patients with refractory ischemia, Dr. Timothy D. Henry said at a conference on cell therapy and cardiovascular diseases.

Many patients with severe coronary artery disease experience persistent, disabling angina despite the use of antianginal drugs and mechanical revascularization, and few good options exist for these patients at present, according to Dr. Henry, who is chief of research, Minneapolis Heart Research Foundation, Minneapolis.

Preclinical studies suggested that neovascularization is possible in chronic ischemia following the administration of autologous endothelial progenitor cells, and particularly when cells expressing the CD34+ marker were used. A pilot study has now provided evidence that such an approach is safe and may result in symptomatic improvements in angina symptoms, Dr. Henry said.

The double-blind, placebo-controlled study included 24 patients comprising 5 women and 19 men, whose mean age was 62 years. All had Canadian Cardiovascular Society (CCS) class III or IV angina, were not candidates for conventional revascularization, had failed on optimal medical therapy, and were on at least two antianginal medications.

Initially all patients underwent stem cell mobilization with the administration of granulocyte colony-stimulating factor for 5 days, at which time leukapheresis was performed and the CD34+ fraction of mononuclear cells were isolated.

They then underwent cardiac navigation using NOGA electromechanical mapping and intramyocardial injection of the CD34+ cells or placebo into the ischemic zone, and were followed for 12 months.

The treatment was well tolerated, with no serious adverse events being attributed to the cell therapy, Dr. Henry said. One patient in the placebo group developed ventricular tachycardia during the mapping procedure, but was cardioverted successfully.

At 3 months, the number of episodes of angina per week fell from 21 to 10 in the treated group, and rose from 21 to 27 in the placebo group. By 6 months, the number of episodes per week had fallen to 9 and 16 in the treated and placebo groups, respectively (Circulation 2007;115:3165–72).

By 6 months, 50% of patients in the treated group had experienced an improvement by at least two CCS classes, as had 33% of placebo patients.

Results on single-photon emission computed tomography (SPECT) were mixed, showing some improvement at 3 months but none at 6 months, Dr. Henry said. “One of the things holding us back in treating patients with chronic refractory ischemia is the lack of a gold standard to measure myocardial blood flow,” he said.

Moreover, improvements in exercise tolerance were modest at best, increasing 0.3 minutes and 0.5 minutes in the placebo and active treatment groups at 3 months, respectively.

Previous trials of various therapies for refractory angina also have failed to demonstrate improvements in exercise tolerance. For example, in an analysis of pooled data from the Angiogenic gene therapy (AGENT) 3 and 4 studies, which evaluated the intracoronary administration of Ad5FGF-4 in patients with chronic angina, there was no significant difference between the active treatment and placebo on the primary end point of change from baseline exercise time at 12 weeks. However, the incidence of angina and worsening angina was significantly less in patients receiving the gene therapy, at 18%, compared with those receiving placebo, at 25% (J. Am. Coll. Cardiol. 2007;50:1038–46).

“As far as placebo-controlled trials that show improvement in exercise time in patients with refractory angina, for angiogenesis there are none, for enhanced external counterpulsation there have been none, for percutaneous transmyocardial laser revascularization there have been none, and for novel drug therapy, there have been none,” Dr. Henry said. “If you ask the patients what the problem is, they say it's chest pain.”

Therefore, a larger randomized trial of CD34+ stem cells that has recently completed enrollment has, as its primary efficacy end point, frequency of angina episodes.

The study protocol calls for 150 patients aged 21–80 years who have CCS functional class III or IV refractory angina. Following the intramyocardial injection of autologous stem cells or placebo, patients will be followed up with MRI and SPECT at 6 and 12 months.

“It's important to remember that this is a very challenging patient population, where bypass didn't work, PCI didn't work, and medical therapy didn't work, and for whom we don't have great options now. Will CD34+ therapy be a better option? Certainly the phase I trial was suggestive, and we're excited about seeing the results of the phase II trial,” said Dr. Henry, who is a consultant to Baxter Healthcare, the study sponsor.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The adolescent HIV-1 epidemic as reflected in a multisite cohort of U.S. youth is changing from one of vertically transmitted infection to one where infection is acquired through risk behaviors, posing new challenges for providers and the health care system, Dr. Allison L. Agwu reported in a poster session at the 15th Conference on Retroviruses and Opportunistic Infections.

The HIV Research Network, a consortium of 21 clinical sites that provide primary HIV care, includes 684 patients aged 12–24 years. Vertical transmission was the source of infection in 227 patients, while risk behaviors account for 457 cases, according to Dr. Agwu of Johns Hopkins University, Baltimore.

Analysis of data from this cohort showed that patients infected through risk behaviors are older, with a median age of 22 years, compared with a median age of 15 years among vertical-transmission patients.

They also are more likely to be male. A total of 292 (64%) of the risk-behavior patients are male, as are 108 (48%) of the vertical-transmission patients.

Risk behaviors comprised men having sex with men (51%), unprotected heterosexual activity (45%), and intravenous drug use (4%).

The median CD4 count in the risk-behavior group was 492 cells/mm

The median HIV RNA level in the risk-behavior group was 6,700 copies/mL, compared with 400 copies/mL in the vertical-transmission group.

Despite this worse immune suppression and higher levels of viremia among the risk-behavior patients, they were less likely to be on highly active antiretroviral therapy (HAART) (43% versus 88%), Dr. Agwu found.

Those infected through risk behaviors also had significantly fewer outpatient visits, averaging five visits per year, while vertical-transmission patients averaged seven visits.

Rates of hospitalization did not differ, at 19/100 patient-years in the risk-behavior group and 17/100 patient-years in the vertical-transmission group, Dr. Agwu reported at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Other aspects of treatment also did not differ significantly between the two groups. For example, 89% of patients meeting the criteria for prophylaxis against Pneumocystis carinii pneumonia in the risk-behavior group received prophylaxis, as did 80% of vertical-transmission patients.

Prophylaxis against Mycobacterium avium complex recommendations were followed by 83% and 75% of those in the risk-behavior and vertical-transmission groups, respectively.

“We suspect that there may be differences in psychosocial risk factors between the two groups that may account for the varying rates of HAART utilization,” Dr. Agwu said in an interview.

“Our future questions will focus on deciphering both patient and provider barriers to HAART initiation in the risk behavior group in order to institute appropriate interventions,” she said.

Dr. Agwu added that this group of patients in need of treatment is likely to grow in number as the Centers for Disease Control and Prevention's recommendation of universal opt-out testing is implemented.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The adolescent HIV-1 epidemic as reflected in a multisite cohort of U.S. youth is changing from one of vertically transmitted infection to one where infection is acquired through risk behaviors, posing new challenges for providers and the health care system, Dr. Allison L. Agwu reported in a poster session at the 15th Conference on Retroviruses and Opportunistic Infections.

The HIV Research Network, a consortium of 21 clinical sites that provide primary HIV care, includes 684 patients aged 12–24 years. Vertical transmission was the source of infection in 227 patients, while risk behaviors account for 457 cases, according to Dr. Agwu of Johns Hopkins University, Baltimore.

Analysis of data from this cohort showed that patients infected through risk behaviors are older, with a median age of 22 years, compared with a median age of 15 years among vertical-transmission patients.

They also are more likely to be male. A total of 292 (64%) of the risk-behavior patients are male, as are 108 (48%) of the vertical-transmission patients.

Risk behaviors comprised men having sex with men (51%), unprotected heterosexual activity (45%), and intravenous drug use (4%).

The median CD4 count in the risk-behavior group was 492 cells/mm

The median HIV RNA level in the risk-behavior group was 6,700 copies/mL, compared with 400 copies/mL in the vertical-transmission group.

Despite this worse immune suppression and higher levels of viremia among the risk-behavior patients, they were less likely to be on highly active antiretroviral therapy (HAART) (43% versus 88%), Dr. Agwu found.

Those infected through risk behaviors also had significantly fewer outpatient visits, averaging five visits per year, while vertical-transmission patients averaged seven visits.

Rates of hospitalization did not differ, at 19/100 patient-years in the risk-behavior group and 17/100 patient-years in the vertical-transmission group, Dr. Agwu reported at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Other aspects of treatment also did not differ significantly between the two groups. For example, 89% of patients meeting the criteria for prophylaxis against Pneumocystis carinii pneumonia in the risk-behavior group received prophylaxis, as did 80% of vertical-transmission patients.

Prophylaxis against Mycobacterium avium complex recommendations were followed by 83% and 75% of those in the risk-behavior and vertical-transmission groups, respectively.

“We suspect that there may be differences in psychosocial risk factors between the two groups that may account for the varying rates of HAART utilization,” Dr. Agwu said in an interview.

“Our future questions will focus on deciphering both patient and provider barriers to HAART initiation in the risk behavior group in order to institute appropriate interventions,” she said.

Dr. Agwu added that this group of patients in need of treatment is likely to grow in number as the Centers for Disease Control and Prevention's recommendation of universal opt-out testing is implemented.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The adolescent HIV-1 epidemic as reflected in a multisite cohort of U.S. youth is changing from one of vertically transmitted infection to one where infection is acquired through risk behaviors, posing new challenges for providers and the health care system, Dr. Allison L. Agwu reported in a poster session at the 15th Conference on Retroviruses and Opportunistic Infections.

The HIV Research Network, a consortium of 21 clinical sites that provide primary HIV care, includes 684 patients aged 12–24 years. Vertical transmission was the source of infection in 227 patients, while risk behaviors account for 457 cases, according to Dr. Agwu of Johns Hopkins University, Baltimore.

Analysis of data from this cohort showed that patients infected through risk behaviors are older, with a median age of 22 years, compared with a median age of 15 years among vertical-transmission patients.

They also are more likely to be male. A total of 292 (64%) of the risk-behavior patients are male, as are 108 (48%) of the vertical-transmission patients.

Risk behaviors comprised men having sex with men (51%), unprotected heterosexual activity (45%), and intravenous drug use (4%).

The median CD4 count in the risk-behavior group was 492 cells/mm

The median HIV RNA level in the risk-behavior group was 6,700 copies/mL, compared with 400 copies/mL in the vertical-transmission group.

Despite this worse immune suppression and higher levels of viremia among the risk-behavior patients, they were less likely to be on highly active antiretroviral therapy (HAART) (43% versus 88%), Dr. Agwu found.

Those infected through risk behaviors also had significantly fewer outpatient visits, averaging five visits per year, while vertical-transmission patients averaged seven visits.

Rates of hospitalization did not differ, at 19/100 patient-years in the risk-behavior group and 17/100 patient-years in the vertical-transmission group, Dr. Agwu reported at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Other aspects of treatment also did not differ significantly between the two groups. For example, 89% of patients meeting the criteria for prophylaxis against Pneumocystis carinii pneumonia in the risk-behavior group received prophylaxis, as did 80% of vertical-transmission patients.

Prophylaxis against Mycobacterium avium complex recommendations were followed by 83% and 75% of those in the risk-behavior and vertical-transmission groups, respectively.

“We suspect that there may be differences in psychosocial risk factors between the two groups that may account for the varying rates of HAART utilization,” Dr. Agwu said in an interview.

“Our future questions will focus on deciphering both patient and provider barriers to HAART initiation in the risk behavior group in order to institute appropriate interventions,” she said.

Dr. Agwu added that this group of patients in need of treatment is likely to grow in number as the Centers for Disease Control and Prevention's recommendation of universal opt-out testing is implemented.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The increased survival among HIV-infected children seen with effective prevention of perinatal transmission and the widespread adoption of highly active antiretroviral therapy has been accompanied by the emergence of a new generation of clinical, public health, and social challenges.

The median age of more than 3,500 infected children followed at U.S. clinical trial sites is now 15 years, and some patients are in their early 20s. The median age at death—9 years in 1994—had risen to 18 years by 2006, said Dr. Lynne Mofenson, chief of the Pediatric, Adolescent, and Maternal AIDS Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md.

Although mortality has decreased, it remains 30 times higher for HIV-infected children than for uninfected children. There also has been a shift in causes of death, with fewer children dying from AIDS-related opportunistic infections and central nervous system disease and more succumbing to end-stage AIDS with multiple organ failure, or to sepsis or renal failure, Dr. Mofenson said at the 15th Conference on Retroviruses and Opportunistic Infections.

Aside from the disease itself, these young patients and their caregivers today face multiple challenges including drug resistance, complications of therapy, and issues related to adherence and mental health, Dr. Mofenson said.

Several studies have found an increase in primary drug resistance among newly infected infants. For instance, data from New York State showed a 58% increase in resistance between 1998 and 2002, reaching 19%. This was primarily accounted for by mutations conferring resistance to the nonnucleoside reverse transcriptase inhibitors (J. Acquir. Immune Defic. Syndr. 2006;42:614–9).

Another series found resistance among 24% of infected children, with 10% being resistant to at least two classes of antiretroviral drugs, Dr. Mofenson said at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Multidrug resistance is a particular problem for older children who were treated with monotherapy or dual therapy before triple therapy became the standard of care. Few choices remain for these children, particularly because many drugs available for adult patients have no pediatric formulations or dosing guidelines. “Without additional drugs, some HIV-infected children will run out of treatment options at a very early age,” Dr. Mofenson said.

Investigations by the Pediatric Spectrum of Disease Project found that in 2001, 44% of children had already received two or more highly active antiretroviral treatment (HAART) regimens, and 3% had received five or more regimens. “This is only going to increase over time,” she said.

These children increasingly face potentially severe complications of long-term therapy, particularly during puberty when as yet unidentified physiologic changes appear to result in the development of hypercholesterolemia, which has been reported in up to 67% of children on therapy, and lipodystrophy, which has been reported in up to 47%.

Additionally, in one series, hyperinsulinemia was found in 60% of children, although insulin resistance was uncommon, she said.

Risk factors that have been identified for the development of these metabolic abnormalities include duration of antiretroviral therapy and the use of protease inhibitors and nucleoside reverse transcriptase inhibitors, particularly ritonavir, Dr. Mofenson said.

These findings further raise concerns about the potential for long-term cardiac complications. In one study from England, carotid intima thickness was significantly greater among 83 HIV-infected children, compared with a control group of 59 healthy children (Circulation 2005;112:103–9).

In that study, preatherosclerotic changes were particularly pronounced among patients treated with protease inhibitors. There may be roles for both HIV infection itself and intermittent antiretroviral therapy in the development of cardiovascular complications, she said.

Another area that is becoming important in pediatric HIV is mental health.

“These children are born into families with multiple stresses including drug use and poverty,” Dr. Mofenson said. In one series of more than 300 children, the prevalence of attention-deficit/hyperactivity disorder was 24%, sixfold higher than in the general population of children, she said. Additionally, 29% had an anxiety disorder, which is a fourfold increase compared with healthy children, and 25% had clinical depression, which is a sevenfold increase.

“Finally, there is the overall challenge of HIV in adolescence,” she said. Many adolescents do not know they are infected, either because their perinatal infection has not been disclosed to them or they are at risk but have not been tested.

And adherence to complex, lifelong therapy can present many difficulties, particularly in young patients who may appear well.

Infected adolescents also increasingly represent a high-risk population for HIV transmission. It has been estimated that 40%–60% of infected adolescents engage in unprotected sex, and there are high rates of substance abuse and smoking as well, she said.

Another disturbing finding that is emerging involves discrepancies in the use of HAART between children who were perinatally infected and those who were infected through risky sex.

“And of course HIV infection is a worldwide public health challenge that disproportionately affects children living in the poorest parts of the world. Infected children in high-resource settings such as the United States represent only 1% of the 2.3 million infected children worldwide,” Dr. Mofenson commented.

BOSTON — The increased survival among HIV-infected children seen with effective prevention of perinatal transmission and the widespread adoption of highly active antiretroviral therapy has been accompanied by the emergence of a new generation of clinical, public health, and social challenges.

The median age of more than 3,500 infected children followed at U.S. clinical trial sites is now 15 years, and some patients are in their early 20s. The median age at death—9 years in 1994—had risen to 18 years by 2006, said Dr. Lynne Mofenson, chief of the Pediatric, Adolescent, and Maternal AIDS Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md.

Although mortality has decreased, it remains 30 times higher for HIV-infected children than for uninfected children. There also has been a shift in causes of death, with fewer children dying from AIDS-related opportunistic infections and central nervous system disease and more succumbing to end-stage AIDS with multiple organ failure, or to sepsis or renal failure, Dr. Mofenson said at the 15th Conference on Retroviruses and Opportunistic Infections.

Aside from the disease itself, these young patients and their caregivers today face multiple challenges including drug resistance, complications of therapy, and issues related to adherence and mental health, Dr. Mofenson said.

Several studies have found an increase in primary drug resistance among newly infected infants. For instance, data from New York State showed a 58% increase in resistance between 1998 and 2002, reaching 19%. This was primarily accounted for by mutations conferring resistance to the nonnucleoside reverse transcriptase inhibitors (J. Acquir. Immune Defic. Syndr. 2006;42:614–9).

Another series found resistance among 24% of infected children, with 10% being resistant to at least two classes of antiretroviral drugs, Dr. Mofenson said at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Multidrug resistance is a particular problem for older children who were treated with monotherapy or dual therapy before triple therapy became the standard of care. Few choices remain for these children, particularly because many drugs available for adult patients have no pediatric formulations or dosing guidelines. “Without additional drugs, some HIV-infected children will run out of treatment options at a very early age,” Dr. Mofenson said.

Investigations by the Pediatric Spectrum of Disease Project found that in 2001, 44% of children had already received two or more highly active antiretroviral treatment (HAART) regimens, and 3% had received five or more regimens. “This is only going to increase over time,” she said.

These children increasingly face potentially severe complications of long-term therapy, particularly during puberty when as yet unidentified physiologic changes appear to result in the development of hypercholesterolemia, which has been reported in up to 67% of children on therapy, and lipodystrophy, which has been reported in up to 47%.

Additionally, in one series, hyperinsulinemia was found in 60% of children, although insulin resistance was uncommon, she said.

Risk factors that have been identified for the development of these metabolic abnormalities include duration of antiretroviral therapy and the use of protease inhibitors and nucleoside reverse transcriptase inhibitors, particularly ritonavir, Dr. Mofenson said.

These findings further raise concerns about the potential for long-term cardiac complications. In one study from England, carotid intima thickness was significantly greater among 83 HIV-infected children, compared with a control group of 59 healthy children (Circulation 2005;112:103–9).

In that study, preatherosclerotic changes were particularly pronounced among patients treated with protease inhibitors. There may be roles for both HIV infection itself and intermittent antiretroviral therapy in the development of cardiovascular complications, she said.

Another area that is becoming important in pediatric HIV is mental health.

“These children are born into families with multiple stresses including drug use and poverty,” Dr. Mofenson said. In one series of more than 300 children, the prevalence of attention-deficit/hyperactivity disorder was 24%, sixfold higher than in the general population of children, she said. Additionally, 29% had an anxiety disorder, which is a fourfold increase compared with healthy children, and 25% had clinical depression, which is a sevenfold increase.

“Finally, there is the overall challenge of HIV in adolescence,” she said. Many adolescents do not know they are infected, either because their perinatal infection has not been disclosed to them or they are at risk but have not been tested.

And adherence to complex, lifelong therapy can present many difficulties, particularly in young patients who may appear well.

Infected adolescents also increasingly represent a high-risk population for HIV transmission. It has been estimated that 40%–60% of infected adolescents engage in unprotected sex, and there are high rates of substance abuse and smoking as well, she said.

Another disturbing finding that is emerging involves discrepancies in the use of HAART between children who were perinatally infected and those who were infected through risky sex.

“And of course HIV infection is a worldwide public health challenge that disproportionately affects children living in the poorest parts of the world. Infected children in high-resource settings such as the United States represent only 1% of the 2.3 million infected children worldwide,” Dr. Mofenson commented.

BOSTON — The increased survival among HIV-infected children seen with effective prevention of perinatal transmission and the widespread adoption of highly active antiretroviral therapy has been accompanied by the emergence of a new generation of clinical, public health, and social challenges.

The median age of more than 3,500 infected children followed at U.S. clinical trial sites is now 15 years, and some patients are in their early 20s. The median age at death—9 years in 1994—had risen to 18 years by 2006, said Dr. Lynne Mofenson, chief of the Pediatric, Adolescent, and Maternal AIDS Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md.

Although mortality has decreased, it remains 30 times higher for HIV-infected children than for uninfected children. There also has been a shift in causes of death, with fewer children dying from AIDS-related opportunistic infections and central nervous system disease and more succumbing to end-stage AIDS with multiple organ failure, or to sepsis or renal failure, Dr. Mofenson said at the 15th Conference on Retroviruses and Opportunistic Infections.

Aside from the disease itself, these young patients and their caregivers today face multiple challenges including drug resistance, complications of therapy, and issues related to adherence and mental health, Dr. Mofenson said.

Several studies have found an increase in primary drug resistance among newly infected infants. For instance, data from New York State showed a 58% increase in resistance between 1998 and 2002, reaching 19%. This was primarily accounted for by mutations conferring resistance to the nonnucleoside reverse transcriptase inhibitors (J. Acquir. Immune Defic. Syndr. 2006;42:614–9).

Another series found resistance among 24% of infected children, with 10% being resistant to at least two classes of antiretroviral drugs, Dr. Mofenson said at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Multidrug resistance is a particular problem for older children who were treated with monotherapy or dual therapy before triple therapy became the standard of care. Few choices remain for these children, particularly because many drugs available for adult patients have no pediatric formulations or dosing guidelines. “Without additional drugs, some HIV-infected children will run out of treatment options at a very early age,” Dr. Mofenson said.

Investigations by the Pediatric Spectrum of Disease Project found that in 2001, 44% of children had already received two or more highly active antiretroviral treatment (HAART) regimens, and 3% had received five or more regimens. “This is only going to increase over time,” she said.

These children increasingly face potentially severe complications of long-term therapy, particularly during puberty when as yet unidentified physiologic changes appear to result in the development of hypercholesterolemia, which has been reported in up to 67% of children on therapy, and lipodystrophy, which has been reported in up to 47%.

Additionally, in one series, hyperinsulinemia was found in 60% of children, although insulin resistance was uncommon, she said.

Risk factors that have been identified for the development of these metabolic abnormalities include duration of antiretroviral therapy and the use of protease inhibitors and nucleoside reverse transcriptase inhibitors, particularly ritonavir, Dr. Mofenson said.

These findings further raise concerns about the potential for long-term cardiac complications. In one study from England, carotid intima thickness was significantly greater among 83 HIV-infected children, compared with a control group of 59 healthy children (Circulation 2005;112:103–9).

In that study, preatherosclerotic changes were particularly pronounced among patients treated with protease inhibitors. There may be roles for both HIV infection itself and intermittent antiretroviral therapy in the development of cardiovascular complications, she said.

Another area that is becoming important in pediatric HIV is mental health.

“These children are born into families with multiple stresses including drug use and poverty,” Dr. Mofenson said. In one series of more than 300 children, the prevalence of attention-deficit/hyperactivity disorder was 24%, sixfold higher than in the general population of children, she said. Additionally, 29% had an anxiety disorder, which is a fourfold increase compared with healthy children, and 25% had clinical depression, which is a sevenfold increase.

“Finally, there is the overall challenge of HIV in adolescence,” she said. Many adolescents do not know they are infected, either because their perinatal infection has not been disclosed to them or they are at risk but have not been tested.

And adherence to complex, lifelong therapy can present many difficulties, particularly in young patients who may appear well.

Infected adolescents also increasingly represent a high-risk population for HIV transmission. It has been estimated that 40%–60% of infected adolescents engage in unprotected sex, and there are high rates of substance abuse and smoking as well, she said.

Another disturbing finding that is emerging involves discrepancies in the use of HAART between children who were perinatally infected and those who were infected through risky sex.

“And of course HIV infection is a worldwide public health challenge that disproportionately affects children living in the poorest parts of the world. Infected children in high-resource settings such as the United States represent only 1% of the 2.3 million infected children worldwide,” Dr. Mofenson commented.

BOSTON — Overweight patients with early rheumatoid arthritis were less likely to achieve remission during treatment with conventional disease-modifying drugs than were those with a normal body mass index.

Overweight and obese patients fared better on a regimen that included infliximab, Dr. Marjatta Leirisalo-Repo, professor of rheumatology at Helsinki University Central Hospital and the University of Helsinki, said at the annual meeting of the American College of Rheumatology.

The study enrolled 100 patients with rheumatoid arthritis (RA) of less than 1 year's duration from 15 centers, randomizing them to methotrexate, sulfasalazine, hydroxychloroquine, and prednisone plus either infliximab or placebo for 6 months. Mean age was 46 years, median symptom duration was 4 months, mean number of swollen joints was 15 and of tender joints, 20. All had morning stiffness of 45 minutes or more. The mean baseline erythrocyte sedimentation rate (ESR) was 33 mm/hr and mean Health Assessment Questionnaire (HAQ) score was 1. In all, 67% were female and 68% were rheumatoid factor positive. None had prior disease-modifying antirheumatic drug (DMARD) treatment.

The DMARD regimens were individually tailored, with maximum dosages of methotrexate of 25 mg/wk and maximum dosages of sulfasalazine of 2 g/day. Hydroxychloroquine was given in dosages of 35 mg/kg a week and prednisone in dosages of 7.5 mg/day. Patients randomized to receive infliximab had the tumor necrosis factor blocker in dosages of 3 mg/kg at weeks 4, 6, 10, 18, and 26. Remission was defined as less than 15 minutes of morning stiffness; no fatigue or painful, swollen, or tender joints; and an ESR less than 30 mm/h.

At 6 months, an overall total of 53% of patients had achieved remission. The percentages of patients in remission at 6 months in the infliximab and placebo groups were 58% and 47%, respectively (58% and 52% at 12 months).

At 6 months, 63% of placebo patients with a body mass index (BMI) of less than 25 kg/m

Obesity is associated with a lack of response to conventional DMARDs, but infliximab was able to overcome this resistance, said Dr. Leirisalo-Repo, who disclosed she has received research grants from Schering-Plough Oy in Finland.

BOSTON — Overweight patients with early rheumatoid arthritis were less likely to achieve remission during treatment with conventional disease-modifying drugs than were those with a normal body mass index.

Overweight and obese patients fared better on a regimen that included infliximab, Dr. Marjatta Leirisalo-Repo, professor of rheumatology at Helsinki University Central Hospital and the University of Helsinki, said at the annual meeting of the American College of Rheumatology.

The study enrolled 100 patients with rheumatoid arthritis (RA) of less than 1 year's duration from 15 centers, randomizing them to methotrexate, sulfasalazine, hydroxychloroquine, and prednisone plus either infliximab or placebo for 6 months. Mean age was 46 years, median symptom duration was 4 months, mean number of swollen joints was 15 and of tender joints, 20. All had morning stiffness of 45 minutes or more. The mean baseline erythrocyte sedimentation rate (ESR) was 33 mm/hr and mean Health Assessment Questionnaire (HAQ) score was 1. In all, 67% were female and 68% were rheumatoid factor positive. None had prior disease-modifying antirheumatic drug (DMARD) treatment.

The DMARD regimens were individually tailored, with maximum dosages of methotrexate of 25 mg/wk and maximum dosages of sulfasalazine of 2 g/day. Hydroxychloroquine was given in dosages of 35 mg/kg a week and prednisone in dosages of 7.5 mg/day. Patients randomized to receive infliximab had the tumor necrosis factor blocker in dosages of 3 mg/kg at weeks 4, 6, 10, 18, and 26. Remission was defined as less than 15 minutes of morning stiffness; no fatigue or painful, swollen, or tender joints; and an ESR less than 30 mm/h.

At 6 months, an overall total of 53% of patients had achieved remission. The percentages of patients in remission at 6 months in the infliximab and placebo groups were 58% and 47%, respectively (58% and 52% at 12 months).

At 6 months, 63% of placebo patients with a body mass index (BMI) of less than 25 kg/m

Obesity is associated with a lack of response to conventional DMARDs, but infliximab was able to overcome this resistance, said Dr. Leirisalo-Repo, who disclosed she has received research grants from Schering-Plough Oy in Finland.

BOSTON — Overweight patients with early rheumatoid arthritis were less likely to achieve remission during treatment with conventional disease-modifying drugs than were those with a normal body mass index.

Overweight and obese patients fared better on a regimen that included infliximab, Dr. Marjatta Leirisalo-Repo, professor of rheumatology at Helsinki University Central Hospital and the University of Helsinki, said at the annual meeting of the American College of Rheumatology.

The study enrolled 100 patients with rheumatoid arthritis (RA) of less than 1 year's duration from 15 centers, randomizing them to methotrexate, sulfasalazine, hydroxychloroquine, and prednisone plus either infliximab or placebo for 6 months. Mean age was 46 years, median symptom duration was 4 months, mean number of swollen joints was 15 and of tender joints, 20. All had morning stiffness of 45 minutes or more. The mean baseline erythrocyte sedimentation rate (ESR) was 33 mm/hr and mean Health Assessment Questionnaire (HAQ) score was 1. In all, 67% were female and 68% were rheumatoid factor positive. None had prior disease-modifying antirheumatic drug (DMARD) treatment.

The DMARD regimens were individually tailored, with maximum dosages of methotrexate of 25 mg/wk and maximum dosages of sulfasalazine of 2 g/day. Hydroxychloroquine was given in dosages of 35 mg/kg a week and prednisone in dosages of 7.5 mg/day. Patients randomized to receive infliximab had the tumor necrosis factor blocker in dosages of 3 mg/kg at weeks 4, 6, 10, 18, and 26. Remission was defined as less than 15 minutes of morning stiffness; no fatigue or painful, swollen, or tender joints; and an ESR less than 30 mm/h.

At 6 months, an overall total of 53% of patients had achieved remission. The percentages of patients in remission at 6 months in the infliximab and placebo groups were 58% and 47%, respectively (58% and 52% at 12 months).

At 6 months, 63% of placebo patients with a body mass index (BMI) of less than 25 kg/m

Obesity is associated with a lack of response to conventional DMARDs, but infliximab was able to overcome this resistance, said Dr. Leirisalo-Repo, who disclosed she has received research grants from Schering-Plough Oy in Finland.